DE69736233T2 - PYRIDOBENZOXAZINDERIVATE - Google Patents

Abstract

This invention provides a derivative, and an excellent pharmaceutical preparation, which has strong antibacterial activity against Gram-negative and Gram-positive bacteria and shows both excellent pharmacokinetics and high safety. Particularly, it provides a pyridobenzoxazine derivative represented by formula (I): <CHEM> wherein R<1>: a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, in which said alkyl group may have a substituent selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms; R<2>: a hydrogen atom or an amino group, in which said amino group may have one or two substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 6 carbon atoms; R<3>: a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group; and a salt thereof or a hydrate thereof, or an antibacterial agent containing the same as its active ingredient.

Description

technical area

The The present invention relates to a pyridobenzoxazine derivative having a 1-amino-3-azabicyclo [3.1.0] hexan-3-yl group as a substituent, which has excellent antibacterial activity, good Pharmacokinetics and high safety, as well as a drug, an antibacterial agent and an antibacterial preparation, containing this compound.

State of technology

since The discovery of norfloxacin has been shown to have antibacterial activity and pharmacokinetics of quinolone-based antibacterial agents improved and today many compounds are in the clinical field used as chemotherapeutic agents in almost all systemic infectious Diseases are effective.

In In recent years, the increase of bacteria has been low sensitivity across from have quinolone-based antibacterial agents, in clinical Area to a problem. For example, in the case of Staphylococcus aureus (MRSA) that does not respond to β-lactam antibiotics addresses the cases increased in which a bacterium that was originally against medicines resistant to quinolone antibacterial agents are different, a low sensitivity to antibacterial agents quinolone-based. Thus, there is a need for development an active substance, which also has the higher efficacy in the clinical area Has.

On The other side has been found to be antibacterial Quinolone-based agents cause a side effect caused by the cramps if not a steroids anti-inflammatory Medicines taken at the same time as well as other side effects like phototoxicity and the like, so that the development of an antibacterial Quinolone based with higher Safety was also required in this area.

Quinolonecarboxylic acid derivatives, the one derived from 3-azabicyclo [3.1.0] hexylamine substituents as in the present invention, for example in JP-A-64-56673 and JP-A-7-48367 (the term "JP-A" as used herein) stands for an "unaudited, published Japanese patent application ") disclosed. Although this one represented by the following formula Discloses compounds only compounds with a quinolone skeleton are described, but there are no compounds with a pyridobenzoxazine skeleton of the present Invention, later is described.

(In der obigen Formel stehen A, R³, R⁶, R⁷, R⁹, R¹⁰, R²⁵, R', W und Y für verschiedene Substituenten wie eine Alkylgruppe. In diesem Zusammenhang ist die Definition von Substituenten, die sich auf die obige Verbindung bezieht, unabhängig von der der Verbindung der vorliegenden Erfindung.)Also, JP-A-3-86875 and JP-A-7-149758 disclose compounds represented by the following formula, but concretely, they do not disclose a compound of the present invention.

(In the above formula, A, R ^3, R ^6, R ^7, R ^9, R ^10, R ^25, R ', W and Y are various substituents such as an alkyl group. In this connection the definition of substituents which may be refers to the above compound, regardless of the compound of the present invention.)

(In den Verbindungen der Formel (A) ist die Definition der Substituenten, die sich auf die obige Verbindung bezieht, unabhängig von der der Verbindung der vorliegenden Erfindung.)Furthermore, JP-A-3-86875 and JP-A-7-149758 disclose the compounds represented by the following formula (A) which have a pyridobenzoxazine skeleton. Although pyridobenzoxazine derivatives having a 6-amino-3-azabicyclo [3.1.0] hexan-3-yl group as a substituent at the 10-position are concretely described in these publications, there is no concrete description regarding pyridobenzoxazine derivatives of the present invention having a 1-amino-3-aczabicyclo [3.1.0] hexan-3-yl group as a substituent in the 10-position. In addition, there is no description herein regarding the excellent pharmacokinetics and safety of the pyridobenzoxazine compounds of the present invention having the 1-amino-3-azabicyclo [3.1.0] hexan-3-yl group as a substituent in the 10-position.

(In the compounds of the formula (A), the definition of the substituents relating to the above compound is independent of that of the compound of the present invention.)

Disclosure of the invention

in view of of the foregoing are the inventors of the present invention intensive investigations were carried out with the goal of having one Compound with outstanding antibacterial activity, high potency and excellent security. As a result of the Efforts were found that one by the following formula (I) represents pyridobenzoxazine compound of a corresponding, by consider the compound represented by the above formula (A) is, whereby the present invention has been completed.

With In other words, it has been found that by the formula (I) Compound presented a wide and excellent antibacterial Effectiveness against both Gram-negative as well as gram-positive bacteria, in particular a strong antibacterial activity against quinolone-resistant bacteria shows and also excellent pharmacokinetics and safety having.

wobei
R¹ für ein Wasserstoffatom oder eine Alkylgruppe mit 1 bis 6 Kohlenstoffatomen steht, wobei die Alkylgruppe einen Substituenten ausgewählt unter einer Hydroxylgruppe, einem Halogenatom, einer Alkylthiogruppe mit 1 bis 6 Kohlenstoffatomen und einer Alkoxylgruppe mit 1 bis 6 Kohlenstoffatomen, aufweisen kann;
R² für ein Wasserstoffatom oder eine Aminogruppe steht, wobei die Aminogruppe einen oder zwei Substituenten ausgewählt unter einer Formylgruppe, einer Alkylgruppe mit 1 bis 6 Kohlenstoffatomen und einer Acylgruppe mit 2 bis 6 Kohlenstoffatomen, aufweisen kann; und
R³ für ein Wasserstoffatom, eine Phenylgruppe, eine Acetoxymethylgruppe, eine Pivaloyloxymethylgruppe, eine Ethoxycarbonylgruppe, eine Cholingruppe, eine Dimethylaminoethylgruppe, eine 5-Indanylgruppe, eine Phthalidinylgruppe, eine 5-Alkyl-2-oxo-1,3-dioxol-4-ylmethylgruppe, eine 3-Acetoxy-2-oxobutylgruppe, eine Alkylgruppe mit 1 bis 6 Kohlenstoffatomen, eine Alkoxymethylgruppe mit 2 bis 7 Kohlenstoffatomen oder eine Phenylalkylgruppe, bestehend aus einer Alkylengruppe mit 1 bis 6 Kohlenstoffatomen und einer Phenylgruppe, steht;
ein Salz hiervon oder ein Hydrat hiervon.A compound represented by formula (I):

in which
R ^{1 represents} a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may have a substituent selected from a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms;
R ^{2 represents} a hydrogen atom or an amino group, wherein the amino group may have one or two substituents selected from a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 6 carbon atoms; and
R ^{3 is} hydrogen, phenyl, acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyl, choline, dimethylaminoethyl, 5-indanyl, phthalidinyl, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or a phenylalkyl group consisting of an alkylene group having 1 to 6 carbon atoms and a phenyl group;
a salt thereof or a hydrate thereof.

Accordingly The present invention relates to the above-mentioned Formula (I) represented, a salt thereof or a hydrate hereof.

10-(1-Amino-3-azabicyclo(3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, einen Ester hiervon, ein Salz hiervon (der Carbonsäure oder des Esters) oder ein Hydrat hiervon (der Carbonsäure, des Esters, des Salzes der Carbonsäure oder Salzes des Esters), umfassend ein reines Isomer;
eine Verbindung der Formel (I), ein Salz hiervon oder ein Hydrat hiervon, worin R² für eine Aminogruppe steht;
8-Amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure (eine durch die folgende Formel dargestellte Verbindung), einen Ester hiervon, ein Salz hiervon (der Carbonsäure oder des Esters) oder ein Hydrat hiervon (der Carbonsäure, des Esters, des Salzes der Carbonsäure oder des Salzes des Esters);

8-Amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, einen Ester hiervon, ein Salz hiervon (der Carbon säure oder des Esters) oder ein Hydrat hiervon (der Carbonsäure, des Esters, des Salzes der Carbonsäure oder Salzes des Esters), umfassend ein reines Isomer;
eine pharmazeutische Zubereitung, enthaltend als aktiven Bestandteil die durch Formel (I) dargestellte Verbindung, ein Salz hiervon oder ein Hydrat hiervon;
eine pharmazeutische Zubereitung, enthaltend als aktiven Bestandteil die durch Formel (I) dargestellte Verbindung, ein Salz hiervon oder ein Hydrat hiervon, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist;
eine pharmazeutische Zubereitung, enthaltend als aktiven Bestandteil die durch Formel (I) dargestellte Verbindung, ein Salz hiervon oder ein Hydrat hiervon, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist und R² für ein Wasserstoffatom steht;
eine pharmazeutische Zubereitung, enthaltend als aktiven Bestandteil 10-(1-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, einen Ester hiervon, ein Salz hiervon oder ein Hydrat hiervon;
eine pharmazeutische Zubereitung, enthaltend als aktiven Bestandteil 10-(1-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, einen Ester hiervon, ein Salz hiervon oder ein Hydrat hiervon, umfassend ein reines Isomer;
eine pharmazeutische Zubereitung, enthaltend als aktiven Bestandteil die durch Formel (I) dargestellte Verbindung, ein Salz hiervon oder ein Hydrat hiervon, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist und R² für eine Aminogruppe steht;
eine pharmazeutische Zubereitung, enthaltend als aktiven Bestandteil 8-Amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, einen Ester hiervon, ein Salz hiervon oder ein Hydrat hiervon;
eine pharmazeutische Zubereitung, enthaltend als aktiven Bestandteil 8-Amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, einen Ester hiervon, ein Salz hiervon oder ein Hydrat hiervon, umfassend ein reines Isomer;
ein antibakterielles Mittel, enthaltend als aktiven Bestandteil die die durch die Formel (I) dargestellte Verbindung, ein Salz hiervon oder ein Hydrat hiervon;
ein antibakterielles Mittel, enthaltend als aktiven Bestandteil die durch Formel (I) dargestellte Verbindung, ein Salz hiervon oder ein Hydrat hiervon, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist;
ein antibakterielles Mittel, enthaltend als aktiven Bestandteil die durch Formel (I) dargestellte Verbindung, ein Salz hiervon oder ein Hydrat hiervon, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist und R² für ein Wasserstoffatom steht;
ein antibakterielles Mittel, enthaltend als aktiven Bestandteil 10-(1-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, einen Ester hiervon, ein Salz hiervon oder ein Hydrat hiervon;
ein antibakterielles Mittel, enthaltend als aktiven Bestandteil 10-(1-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, einen Ester hiervon, ein Salz hiervon oder ein Hydrat hiervon, umfassend ein reines Isomer;
ein antibakterielles Mittel, enthaltend als aktiven Bestandteil die durch Formel (I) dargestellte Verbindung, ein Salz hiervon oder ein Hydrat hiervon, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist und R² für eine Aminogruppe steht;
ein antibakterielles Mittel, enthaltend als aktiven Bestandteil 8-Amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, einen Ester hiervon, ein Salz hiervon oder ein Hydrat hiervon;
ein antibakterielles Mittel, enthaltend als aktiven Bestandteil 8-Amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, einen Ester hiervon, ein Salz hiervon oder ein Hydrat hiervon, umfassend ein reines Isomer;
die Verwendung einer Verbindung der Formel (I) zur Herstellung eines Medikamentes zur Behandlung von Infektionserkrankungen, umfassend die Verabreichung einer wirksamen Menge der durch Formel (I) dargestellten Verbindung, eines Salzes hiervon oder eines Hydrats hiervon an einen Patienten, der einer solchen Behandlung bedarf;
die Verwendung einer Verbindung der Formel (I) zur Herstellung eines Medikamentes zur Behandlung von Infektionserkrankungen, umfassend die Verabreichung einer wirksamen Menge der durch Formel (I) dargestellten Verbindung, eines Salzes hiervon oder eines Hydrats hiervon, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist, an einen Patienten, der einer solchen Behandlung bedarf;
die Verwendung einer Verbindung der Formel (I) zur Herstellung eines Medikamentes zur Behandlung von Infektionserkrankungen, umfassend die Verabreichung einer wirksamen Menge der durch Formel (I) dargestellten Verbindung, eines Salzes hiervon oder eines Hydrats hiervon, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist und R² für ein Wasserstoffatom steht, an einen Patienten, der einer solchen Behandlung bedarf;
die Verwendung einer Verbindung der Formel (I) zur Herstellung eines Medikamentes zur Behandlung von Infektionserkrankungen, umfassend die Verabreichung einer wirksamen Menge von 10-(1-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, eines Esters hiervon, eines Salzes hiervon oder eines Hydrats hiervon, an einen Patienten, der einer solchen Behandlung bedarf;
die Verwendung einer Verbindung der Formel (I) zur Herstellung eines Medikamentes zur Behandlung von Infektionserkrankungen, umfassend die Verabreichung einer wirksamen Menge von 10-(1-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, eines Esters hiervon, eines Salzes hiervon oder eines Hydrats hiervon, umfassend ein reines Isomer, an einen Patienten, der einer solchen Behandlung bedarf;
die Verwendung einer Verbindung der Formel (I) zur Herstellung eines Medikamentes zur Behandlung von Infektionserkrankungen, umfassend die Verabreichung einer wirksamen Menge der durch Formel (I) dargestellten Verbindung, eines Salzes hiervon oder eines Hydrats hiervon, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist und R² für eine Aminogruppe steht, an einen Patienten, der einer solchen Behandlung bedarf;
die Verwendung einer Verbindung der Formel (I) zur Herstellung eines Medikamentes zur Behandlung von Infektionserkrankungen, umfassend die Verabreichung einer wirksamen Menge von 8-Amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, eines Esters hiervon, eines Salzes hiervon oder eines Hydrats hiervon, an einen Patienten, der einer solchen Behandlung bedarf;
die Verwendung einer Verbindung der Formel (I) zur Herstellung eines Medikamentes zur Behandlung von Infektionserkrankungen, umfassend die Verabreichung eine wirksamen Menge von 8-Amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, eines Esters hiervon, eines Salzes hiervon oder eines Hydrats hiervon, umfassend ein reines Isomer, an einen Patienten, der einer solchen Behandlung bedarf;
die Verwendung der durch Formel (I) dargestellten Verbindung, eines Salzes hiervon oder eines Hydrats hiervon zur Herstellung einer pharmazeutischen Zubereitung;
die Verwendung der durch Formel (I) dargestellten Verbindung, eines Salzes hiervon oder eines Hydrats hiervon zur Herstellung einer pharmazeutischen Zubereitung, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist;
die Verwendung der durch Formel (I) dargestellten Verbindung, eines Salzes hiervon oder eines Hydrats hiervon zur Herstellung einer pharmazeutischen Zubereitung, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist und R² für ein Wasserstoffatom steht;
die Verwendung von 10-(1-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, eines Esters hiervon, eines Salzes hiervon oder eines Hydrats hiervon zur Herstellung einer pharmazeutischen Zubereitung;
die Verwendung von 10-(1-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, eines Esters hiervon, eines Salzes hiervon oder eines Hydrats hiervon, umfassend ein reines Isomer, zur Herstellung einer pharmazeutischen Zubereitung;
die Verwendung der durch die Formel (I) dargestellten Verbindung, eines Salzes hiervon oder eines Hydrats hiervon zur Herstellung einer pharmazeutischen Zubereitung, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist und R² für eine Aminogruppe steht;
die Verwendung von 8-Amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, eines Esters hiervon, eines Salzes hiervon oder eines Hydrats hiervon, zur Herstellung einer pharmazeutischen Zubereitung;
die Verwendung von 8-Amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, eines Esters hiervon, eines Salzes hiervon oder eines Hydrats hiervon, umfassend ein reines Isomer, zur Herstellung einer pharmazeutischen Zubereitung;
die zuvor genannte Verwendung der durch Formel (I) dargestellten Verbindung, eines Salzes hiervon oder eines Hydrats hiervon, wobei die pharmazeutische Zubereitung ein antibakterielles Mittel ist;
die Verwendung der durch Formel (I) dargestellten Verbindung, eines Salzes hiervon oder eines Hydrats hiervon, zur Behandlung von Infektionserkrankungen;
die Verwendung der durch Formel (I) dargestellten Verbindung, eines Salzes hiervon oder eines Hydrats hiervon, zur Behandlung von Infektionserkrankungen, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist;
die Verwendung der durch Formel (I) dargestellten Verbindung, eines Salzes hiervon oder eines Hydrats hiervon, zur Behandlung von Infektionserkrankungen, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist und R² für ein Wasserstoffatom steht;
die Verwendung von 10-(1-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, eines Esters hiervon, eines Salzes hiervon oder eines Hydrats hiervon, zur Behandlung von Infektionserkrankungen;
die Verwendung von 10-(1-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, eines Esters hiervon, eines Salzes hiervon oder eines Hydrats hiervon, umfassend ein reines Isomer, zur Behandlung von Infektionserkrankungen;
die Verwendung der durch Formel (I) dargestellten Verbindung, eines Salzes hiervon oder eines Hydrats hiervon, zur Behandlung von Infektionserkrankungen, worin die Verbindung der Formel (I) eine stereochemisch reine Verbindung ist und R² für eine Aminogruppe steht;
die Verwendung von 8-Amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, eines Esters hiervon, eines Salzes hiervon oder eines Hydrats hiervon, zur Behandlung von Infektionserkrankungen;
und
die Verwendung von 8-Amino-10-(1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-9-fluor-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazin-6-carbonsäure, eines Esters hiervon, eines Salzes hiervon oder eines Hydrats hiervon, umfassend ein reines Isomer, zur Behandlung von Infektionserkrankungen.The present invention also relates to the aforementioned compound, a salt thereof or a hydrate thereof, wherein the compound of the formula (I) is a stereochemically pure compound;
a compound of formula (I), a salt thereof, or a hydrate thereof, wherein R ^{2 is} a hydrogen atom;
10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1, 2,3-de] benzoxazine-6-carboxylic acid (a compound represented by the present formula), an ester thereof, a salt thereof (the carboxylic acid or the ester) or a hydrate thereof (the carboxylic acid, the ester, the salt of the carboxylic acid and salt of the ester);

10- (1-amino-3-azabicyclo (3.1.0] hexane-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1, 2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof (the carboxylic acid or the ester) or a hydrate thereof (the carboxylic acid, the ester, the salt of the carboxylic acid or the salt of the ester) comprising a pure one Isomer;
a compound of formula (I), a salt thereof, or a hydrate thereof, wherein R ^{2 is} an amino group;
8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H- pyrido [1,2,3-de] benzoxazine-6-carboxylic acid (a compound represented by the following formula), an ester thereof, a salt thereof (the carboxylic acid or the ester) or a hydrate thereof (the carboxylic acid, the ester, the salt of the carboxylic acid or the salt of the ester);

8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H- pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof (the carboxylic acid or the ester) or a hydrate thereof (the carboxylic acid, the ester, the salt of the carboxylic acid or the salt of the ester ) comprising a pure isomer;
a pharmaceutical preparation containing as an active ingredient the compound represented by formula (I), a salt thereof or a hydrate thereof;
a pharmaceutical preparation containing as an active ingredient the compound represented by formula (I), a salt thereof or a hydrate thereof, wherein the compound of formula (I) is a stereochemically pure compound;
a pharmaceutical preparation containing as active ingredient the compound represented by formula (I), a salt thereof or a hydrate thereof, wherein the compound of formula (I) is a stereochemically pure compound and R ^{2 is} a hydrogen atom;
A pharmaceutical preparation containing as active ingredient 10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7- oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof;
A pharmaceutical preparation containing as active ingredient 10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7- oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof, comprising a pure isomer;
a pharmaceutical preparation containing as active ingredient the compound represented by formula (I), a salt thereof or a hydrate thereof, wherein the compound of formula (I) is a stereochemically pure compound and R ^{2 is} an amino group;
a pharmaceutical preparation containing as an active ingredient 8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H- pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof;
A pharmaceutical preparation containing as active ingredient 8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) - methyl 7-oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof, comprising a pure isomer;
an antibacterial agent containing as an active ingredient the compound represented by the formula (I), a salt thereof or a hydrate thereof;
an antibacterial agent containing as an active ingredient the compound represented by formula (I), a salt thereof or a hydrate thereof, wherein the compound of formula (I) is a stereochemically pure compound;
an antibacterial agent containing as an active ingredient the compound represented by formula (I), a salt thereof or a hydrate thereof, wherein the compound of formula (I) is a stereochemically pure compound and R ^{2 is} a hydrogen atom;
an antibacterial agent containing as active ingredient 10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7- oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof;
an antibacterial agent containing as active ingredient 10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7- oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof, comprising a pure isomer;
an antibacterial agent containing as an active ingredient the compound represented by formula (I), a salt thereof or a hydrate thereof, wherein the compound of formula (I) is a stereochemically pure compound and R ^{2 is} an amino group;
an antibacterial agent containing as active ingredient 8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) - methyl 7-oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof;
an antibacterial agent containing as active ingredient 8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) - methyl 7-oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof, comprising a pure isomer;
the use of a compound of formula (I) for the manufacture of a medicament for the treatment of infectious diseases comprising administering to a patient in need of such treatment an effective amount of the compound represented by formula (I), a salt thereof or a hydrate thereof;
the use of a compound of formula (I) for the manufacture of a medicament for the treatment of infectious diseases comprising administering an effective amount of the compound represented by formula (I), a salt thereof or a hydrate thereof, wherein the compound of formula (I) has a stereochemically pure compound is to a patient in need of such treatment;
the use of a compound of formula (I) for the manufacture of a medicament for the treatment of infectious diseases comprising administering an effective amount of the compound represented by formula (I), a salt thereof or a hydrate thereof, wherein the compound of formula (I) has a is stereochemically pure compound and R ^{2 is} a hydrogen atom, to a patient in need of such treatment;
the use of a compound of formula (I) for the manufacture of a medicament for the treatment of infectious diseases comprising administering an effective amount of 10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro 2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof a patient in need of such treatment;
the use of a compound of formula (I) for the manufacture of a medicament for the treatment of infectious diseases comprising administering an effective amount of 10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro 2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof a pure isomer to a patient in need of such treatment;
the use of a compound of formula (I) for the manufacture of a medicament for the treatment of infectious diseases comprising administering an effective amount of the compound represented by formula (I), a salt thereof or a hydrate thereof, wherein the compound of formula (I) has a is stereochemically pure compound and R ^{2 is} an amino group, to a patient in need of such treatment;
the use of a compound of formula (I) for the manufacture of a medicament for the treatment of infectious diseases comprising administering an effective amount of 8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H- pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof, to a patient in need of such treatment;
the use of a compound of formula (I) for the manufacture of a medicament for the treatment of infectious diseases comprising administering an effective amount of 8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a Hydrate thereof, comprising a pure isomer, to a patient in need of such treatment;
the use of the compound represented by formula (I), a salt thereof or a hydrate thereof for the preparation of a pharmaceutical preparation;
the use of the compound represented by formula (I), a salt thereof or a hydrate thereof for the preparation of a pharmaceutical preparation, wherein the compound of formula (I) is a stereochemically pure compound;
the use of the compound represented by formula (I), a salt thereof or a hydrate thereof for the preparation of a pharmaceutical preparation, wherein the compound of formula (I) is a stereochemically pure compound and R ^{2 is} a hydrogen atom;
the use of 10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof for the preparation of a pharmaceutical preparation;
the use of 10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof, comprising a pure isomer, for the preparation of a pharmaceutical preparation;
the use of the compound represented by the formula (I), a salt thereof or a hydrate thereof for the preparation of a pharmaceutical preparation, wherein the compound of the formula (I) is a stereochemically pure compound and R ^{2 is} an amino group;
the use of 8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo -7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof, for the preparation of a pharmaceutical preparation;
the use of 8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo -7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof, comprising a pure isomer, for the preparation of a pharmaceutical preparation;
the aforementioned use of the compound represented by formula (I), a salt thereof or a hydrate thereof, wherein the pharmaceutical preparation is an antibacterial agent;
the use of the compound represented by formula (I), a salt thereof or a hydrate thereof for the treatment of infectious diseases;
the use of the compound represented by formula (I), a salt thereof or a hydrate thereof for the treatment of infectious diseases, wherein the compound of formula (I) is a stereochemically pure compound;
the use of the compound represented by formula (I), a salt thereof or a hydrate thereof for the treatment of infectious diseases, wherein the compound of formula (I) is a stereochemically pure compound and R ^{2 is} a hydrogen atom;
the use of 10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof for the treatment of infectious diseases;
the use of 10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof, or a hydrate thereof, comprising a pure isomer, for the treatment of infectious diseases;
the use of the compound represented by formula (I), a salt thereof or a hydrate thereof for the treatment of infectious diseases, wherein the compound of formula (I) is a stereochemically pure compound and R ^{2 is} an amino group;
the use of 8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo 7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof, for the treatment of infectious diseases;
and
the use of 8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo 7H-pyrido [1,2,3-de] benzoxazine-6-carboxylic acid, an ester thereof, a salt thereof or a hydrate thereof send a pure isomer, for the treatment of infectious diseases.

in the Hereinafter, each of the substituents represented by the formula (I) compound of the invention described.

The substituent R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may have a substituent selected from a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms.

The Alkyl group may be straight or branched having 1 to 6 carbon atoms where preferred examples are a methyl group, an ethyl group, an n-propyl group and an isopropyl group. When the alkyl group is substituted with 1 to 6 carbon atoms with hydroxyl, so it may be straight-chain or branched, with a hydroxyethyl group and a hydroxypropyl group are preferred examples.

The substituent R ² represents a hydrogen atom or an amino group, wherein the amino group may have one or two substituents selected from a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 6 carbon atoms.

When the substituent R ^{2 is} an amino group, it may be protected with a commonly used protective group. Typical examples of the protective group are a (substituted) alkoxycarbonyl group such as tert-butoxycarbonyl and 2,2,2-trichloroethoxycarbonyl; a (substituted) aralkyloxycarbonyl group such as benzyloxycarbonyl, paramethoxybenzyloxycarbonyl and paranitrobenzyloxycarbonyl; a (substituted) acyl group such as acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl and benzoyl; a (substituted) alkyl group or a (substituted) aralkyl group such as tert-butyl, benzyl, paranitrobenzyl, paramethoxybenzyl and triphenylmethyl; a (substituted) ether group such as methoxymethyl, tert-butoxymethyl, tetrahydropyranyl and 2,2,2-trichloroethoxymethyl; and a substituted silyl group such as trimethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tribenzylsilyl and tert-butyldiphenylsilyl (trialkylsilyl group and triaralkylsilyl group which may be substituted with various substituents). Compounds having substituents protected with this substituent are particularly useful as manufacturing intermediates. (In this context, the term "(substituted)" as used herein means "which may have a substituent".)

The substituent R ³ represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxole 4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group consisting of an alkylene group having 1 to 6 carbon atoms and a phenyl group.

The Compound of the present invention is characterized by that they have a substituent represented by the following formula in the 10-postition of its pyridobenzoxazine scaffold and thereby, that they have strong antibacterial activity against Gram-negative and Gram-positive bacteria, especially quinolone-resistant bacteria, shows and both excellent pharmacokinetics and safety having. In the substituent of the following formula, the bridgehead carbon atom is (which receives the 1-position), to which the amino group is attached, an asymmetric carbon, such that the substituent, which can be considered as an antipod, exists and compounds differing from these two substituents derive are included in the present invention.

Since diastereomers are present in the compound of formula (I) of the present invention, administration of a compound of the invention to humans and animals is administration of the verbin expediently comprising a pure diastereomer. The term "comprises a pure diastereomer" as used herein means not only a case in which it is completely free of the other diastereomer but also a case in which it is chemically pure. In other words, this term also encompasses that the other diastereomer is present at a level that does not affect the physical constants and physiological activities of the compound.

Also the term used herein "stereochemically pure "means that if a connection is more asymmetric due to the presence Carbon atoms form a plurality of isomeric forms, the compound only one of these covers. The term "pure" can in this case, the same as previously described.

The Pyridobenzoxazincarbonsäure derivative of the present invention may be either in its free form or as an acid addition salt or used as the salt of its carboxyl group. Examples for the acid addition salt are inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide or phosphate; and organic acid salts, such as acetate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, maleate, Fumarate or lactate.

The Salt of the carboxyl group may be either inorganic or organic and typical examples include an inorganic salt such as alkali metal salts (e.g., a lithium salt, a sodium salt and a potassium salt), alkaline earth metal salts (e.g., a magnesium salt and a calcium salt) or ammonium salt; and an organic salt such as a triethylamine salt, an N-methylglucamine salt or a tris (hydroxylmethyl) aminomethane salt.

Besides, these can free form, the acid addition salts and the salts of the carboxyl group of Pyridobenzoxazincarbonsäure derivatives present as hydrates.

on the other hand is a quinolone derivative whose carboxylic acid portion is an ester, as Synthesis intermediate or as a prodrug suitable. For example are alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters and Phenylester useful Synthesis intermediates.

Also For example, the ester used as a prodrug is an ester that is rapidly living body is cleaved to form a free carboxylic acid, wherein concrete Examples acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, Choline esters, dimethylaminoethyl esters, 5-indanyl esters, phthalidinyl esters, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester and an oxoalkyl ester such as 3-acetoxy-2-oxobutyl ester or the like.

worin X für eine Gruppe steht, die als Abgangsgruppe dient, wie ein Fluoratom, eine Chloratom, ein Bromatom, eine Alkylsulfonylgruppe mit 1 bis 3 Kohlenstoffatomen oder eine Arylsulfonylgruppe, wie eine Benzolsulfonylgruppe, eine Toluolsulfonylgruppe; R³ die in Formel (I) für R³ angegebene Bedeutung aufweist oder für eine Bor-enthaltende Gruppe steht, die durch die Formel (IV) dargestellt ist: -B(R⁴)R⁵ (IV)worin R⁴ und R⁵ für ein Fluoratom oder eine Niederalkylcarbonyloxygruppe stehen); und
R² wie in der Formel (I) definiert ist,
mit einer durch Formel (V) dargestellten Verbindung

(worin R¹ wie in Formel (I) definiert ist, abgesehen davon, dass R¹ eine Schutzgruppe Rx des Stickstoffatoms sein kann und die Schutzgruppe Rx eine Gruppe ist, die üblicherweise auf diesem Gebiet verwendet wird, wobei konkrete Beispiele umfassen eine (substituierte) Alkoxycarbonylgruppe, wie eine tertiäre Butoxycarbonylgruppe und eine 2,2,2-Trichlorethoxycarbonylgruppe; eine (substituierte) Aralkyloxycarbonylgruppe, wie eine Benzyloxycarbonylgruppe, eine Paramethoxybenzyloxycarbonylgruppe und eine Paranitrobenzyloxycarbonylgruppe; eine (substituierte) Acylgruppe, wie eine Acetylgruppe, eine Methoxyacetylgruppe, eine Trifluoracetylgruppe, eine Chloracetylgruppe, eine Pivaloylgruppe, eine Formylgruppe und eine Benzoylgruppe; eine (substituierte) Alkylgruppe oder eine (substituierte) Aralkylgruppe, wie eine tertiäre Butylgruppe, eine Benzylgruppe, eine Paranitrobenzylgruppe, eine Paramethoxyben zylgruppe und eine Triphenylmethylgruppe; eine (substituierte) Ethergruppe, wie eine Methoxymethylgruppe, eine tertiäre Gruppe, eine Butoxymethylgruppe, eine Tetrahydropyranylgruppe und eine 2,2,2-Trichlorethoxymethylgruppe; und eine substituierte Silylgruppe, wie eine Trimethylsilylgruppe, eine Isopropyldimethylsilylgruppe, eine tertiäre Butyldimethylsilylgruppe, eine Tribenzylsilylgruppe und eine tertiäre Butyldiphenylsilylgruppe) oder einem Säureadditionssalz hiervon reagieren lässt.The compound of the present invention represented by the formula (I) can be prepared by various methods, and in a preferred example of these methods, it can be prepared by, for example, a compound represented by the formula (III):

wherein X represents a group serving as a leaving group such as a fluorine atom, a chlorine atom, a bromine atom, an alkylsulfonyl group having 1 to 3 carbon atoms or an arylsulfonyl group such as a benzenesulfonyl group, a toluenesulfonyl group; R ^{3 has} the meaning given in formula (I) for R ³ or represents a boron-containing group represented by the formula (IV): -B (R ⁴ ) R ⁵ (IV) wherein R ⁴ and R ^{5 represent} a fluorine atom or a lower alkylcarbonyloxy group); and
R ^{2 is} as defined in the formula (I),
with a compound represented by formula (V)

(wherein R ^{1 is} as defined in formula (I) except that R ^{1 may be} a protecting group Rx of the nitrogen atom and the protecting group Rx is a group commonly used in the field, specific examples of which include (substituted) An alkoxycarbonyl group such as a tertiary butoxycarbonyl group and a 2,2,2-trichloroethoxycarbonyl group; a (substituted) aralkyloxycarbonyl group such as a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group and a paranitrobenzyloxycarbonyl group; a (substituted) acyl group such as an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a chloroacetyl group a (substituted) alkyl group or a (substituted) aralkyl group such as a tertiary butyl group, a benzyl group, a paranitrobenzyl group, a paramethoxybenzyl group and a triphenylmethyl group; a (substituted) ether group such as a metho xymethyl group, a tertiary group, a butoxymethyl group, a tetrahydropyranyl group and a 2,2,2-trichloroethoxymethyl group; and a substituted silyl group such as a trimethylsilyl group, an isopropyldimethylsilyl group, a tertiary butyldimethylsilyl group, a tribenzylsilyl group and a tertiary butyldiphenylsilyl group) or an acid addition salt thereof.

When R ^{3 is} an alkyl group having 1 to 6 carbon atoms, an alkoymethyl group having 2 to 7 carbon atoms or a combination of an alkylene group having 1 to 6 carbon atoms and a phenyl group, the conversion to the corresponding carboxylic acid is carried out under usual acidic or basic conditions for the hydrolysis of a carboxylic acid ester and when deprotection is required, the protecting group is removed under conditions which are conveniently selected for this protecting group to yield the desired compound represented by formula (I).

When R ³ in the compound of the formula (III) is a compound represented by the formula (IV), the conversion into the corresponding carboxylic acid can be effected by reacting after the substitution reaction of the compound of the formula (III) with the compound (V ) performs a treatment with an acidic or basic compound.

The Substitution reaction of the compound of the formula (III) with the compound of the formula (V) can be carried out with or without a solvent. The solvent used is not subject to any particular restrictions as long as it is among the Reaction conditions is inert. Typical examples of suitable solvents include dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, Dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, Water and 3-methoxybutanol. These solvents can be alone or used as a mixture thereof.

The Implementation can usually at a temperature in the range of room temperature to 200 ° C, preferably from 25 to 150 ° C carried out become. The reaction time is 30 minutes to 48 hours and the implementation is generally within a period of 30 minutes to 2 hours completely.

It is advantageous to the reaction in the presence of an inorganic or organic base as an acid acceptor perform, e.g. an inorganic base such as alkali metal carbonates (e.g., lithium carbonate, Sodium carbonate and potassium carbonate), alkaline earth metal carbonates (e.g. Calcium carbonate and magnesium carbonate), alkali metal bicarbonates (e.g., lithium hydrogencarbonate, sodium bicarbonate and potassium bicarbonate) or alkaline earth metal hydrogencarbonates (e.g., calcium hydrogen carbonate and magnesium hydrogencarbonate); and an organic basic compound, such as a trialkylamine (e.g., triethylamine, tributylamine and diisopropylethylamine) or a nitrogen-containing heterocyclic compound (e.g. Pyridine, dimethylaminopyridine, N-alkylmorpholine, N-alkylpiperidine and 1,8-diazabicycloundecene).

Since the compound of the formula (V) has an asymmetric carbon atom, it may be in optically active forms, and its racemic compound may be prepared in accordance with the method described in JP-A-64-56673. In this case, the compound of the formula (I) as the compound of the present invention is a mixture of diastereomers. When the compound of the invention is administered to humans or animals, it is convenient to administer a pure diastereomer. The diastereomeric mixture of the formula (I) of the present invention can be transformed into a pure, individual Separate elles diastereomer by using a known method.

In this context leaves the optically active compound of formula (V) according to various methods and, although not particularly limited it is preferably after that in the reference example produced method produced.

The compound of the present invention has excellent antibacterial activity against Gram-negative and Gram-positive bacteria, and has excellent pharmacokinetics and safety, and among the compounds of the general formula (I), a compound wherein R ^{2 represents} a hydrogen atom or an amino group is suitable or an acid addition salt thereof or a hydrate thereof, and particularly suitable is a compound wherein R ^{2 is} an amino group, or an acid addition salt thereof or a hydrate thereof. Specific examples of the suitable compound are the following:
10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1, 2,3-de] benzoxazine-6-carboxylic acid and
8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H- pyrido [1,2,3-de] benzoxazine-6-carboxylic acid.

There the compound of the invention has strong antibacterial effects, they can be used as active ingredients Use in human bodies, Animals and fish or as a preservative for agricultural Chemicals and food are used.

If the compound of the present invention as an active ingredient for human body is used, their dosage is generally in the range of 50 mg to 1 g, preferably 100 mg to 300 mg, per day per adult.

Your Dosage as active ingredient for Animals are hanging of the purpose of administration (treatment or prevention), the type and size of each animal to be treated and the nature and degree of each infectious pathogenic From the bacterium, the dosage generally being in the range of 1 mg to 200 mg, preferably from 5 mg to 100 mg, per 1 kg of body weight per day.

The Daily dose may be once a day or divided into 2 to 4 dosages be administered per day. If circumstances require, the Daily dose the previously mentioned Pass range.

There the compound of the invention an activity across from a wide range of microorganisms, the most diverse infectious Cause illness, it is for treatment, prevention or alleviation of diseases caused by these pathogens be suitable.

concrete examples for Bacteria and bacteriotic microorganisms against which the compound of the invention are effective, include those belonging to the strain Staphylococcus, Streptococcus pyogens, hemolytic Streptococci, Enterococcus, Pneumococcus include, those belonging to the strain Peptostreptococcus, Neisseria gonorrhoeae, Escherichia coli, include those that belong to the strain Citrobacter, those belonging to the tribe Shigella, Klebsiella pneumoniae, those belonging to the strain Enterobacter, those belonging to the Serratia tribe, those belonging to the tribe Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, belonging to the strain Acinetobacter, those belonging to the strain Campylobacter, Chlamydia trachomatis and the like belong.

concrete examples for Diseases caused by these pathogens include folliculitis, Boils, carbuncle, cutaneous rose, phlegmon, lymphangitis, nail bedding, subcutaneous abscess, hidradenitis, acne conglobata, infectious atheroma, perirectal abscess, mastitis, superficial secondary infection after injury, burn injury, surgical wound and the like, Paryngitis, acute bronchitis, tonsillitis, chronic bronchitis, Bronchiectasis, diffuse bronchiolitis, secondary infection of a chronic respiratory disease, Pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, Gonococcal urethritis, nonspecific Urethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis, uterine adnexitis, intrauterine infection, bartholinitis, blepharitis, Hordeolum, dacryocystitis, tarsadenitis, corneal ulcer, otitis media, sinusitis, perioditis, pericoronitis, jaw infection, Peritonitis, endocarditis, sepsis, meningitis, skin infection and like.

The inventive compound also works against different microorganisms, the infectious diseases in animals, such as those belonging to the strains Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphyloccoccus, Mycoplasma and the like.

concrete examples for such diseases include colibacillosis, pullorum disease in the case of birds, Avian paratyphoid, bird cholera, infectious cold, staphylococcosis, Mycoplasmosis and the like; in the case of pigs Colibacillose, Salmonellosis, Pasteurellosis, Hemophilus infection, arthrophic rhinitis, secreting epidermis, mycoplasmosis and the like; in the case of cattle colibacillosis, salmonellosis, hemorrhagic Sepsis, mycoplasmosis, bovine pleuropneumonia, bovine mastitis and the like; in the case of dogs Colisepsis, salmonellosis, hemorrhagic Sepsis, uterine empyema, cystitis and the like; and in the case of Cats wet pleurisy, Cystitis, chronic rhinitis, hemophilus infection, Catarrh diarrhea, mycoplasmosis and the like.

you For example, the antibacterial preparation containing the compound of the invention contains make one by one for the respective administration method selects suitable preparation and different, commonplace Applies manufacturing methods. With regard to the dosage forms the antibacterial preparation containing the compound of the invention contains as main agent, can Tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous Suspensions and the like serve as examples of oral preparations.

in the Regard to injections a stabilizing agent, an antiseptic agent, a solubilizing agent Means and the like can be used in the preparation, or a solution, which may contain these tools may be contained in a container be converted into a solid preparation by freeze-drying or similar measures, which dissolved when used becomes. Furthermore can be a single dose in a single container or multiple doses in the same container be included.

When examples for Preparations for external applications can also solutions, Suspensions, emulsions, ointments, gels, creams, lotions, sprays and the like.

firm Preparations can pharmaceutically acceptable Contain additives together with the active ingredient and can, for example prepared by mixing the compound with additives, the optional under fillers, Extenders, binders, disintegrants, solubilization promoting Agents, humectants, lubricants and the like are selected.

When examples for liquid Preparations can Solutions, Suspensions, emulsions and the like which are a suspending agent, may contain an emulsifier and the like as additives.

Examples for administration routes the compound of the invention Animals include a method in which they are administered directly or through Mixing with food and the like is orally administered Procedure in which they as a solution is processed and then orally directly or by mixing with drinking water, is administered with food and the like, and a method at which she is given by injection.

For pharmaceutical Compositions for administering the compounds of the invention can be used on animals these optionally as powders, fine subtilae, soluble powders, syrups, solutions or injections, using techniques conventional in the art applies.

formulation Examples for pharmaceutical Preparations are given below.

Production Example 1 (Capsules): Table 1

Production Example 2 (Solutions):

Production Example 3 (powder for mixing with feed):

Best embodiment the invention

The serve as examples of the present invention given below the explanation and are not limiting to understand. In this regard, the antibacterial activity of the particular compound according to the specified by the Japanese Society of Chemotherapy Standard method determined, the results in Table 2 as MIC values (μg / ml) are indicated.

[Reference Example A-1]

N- [2-cyanoethyl) -N - [(1S) -phenylethyl] -3-amino-1,2-propanediol

Glycidol (37 g, 0.5 mol) was added to an ice-bath cooled solution of (S) - (-) - phenylethylamine (75 mL, 0.58 mmol) in ethanol (500 mL) and the mixture stirred for 20 minutes Room temperature and then heated for 62 hours at reflux. Acrylonitrile (40 ml) was added and refluxed again for 45 hours and then the reaction solution was concentrated. The resulting residue was subjected to silica gel chromatography to obtain 121 g (84%) of the title compound from the eluate containing 5% methanol-chloroform.
¹ H-NMR _(CDCl3) δ: 1.41-1.48 (3 H, m), 2.39 to 2.50 (2 H, m), 2.60 to 3.25 (4H, m 3.41-3.46 (1H, m), 3.68-3.78 (2H, m), 3.93-4.02 (1H, m), 7.27-7, 40 (5H, m).

[Reference Example A-2]

N- (2-cyanoethyl) -N - [(1S) -phenylethyl] -3-amino-1,2-dibromopropane

Triphenylphosphine (57.71 g, 0.22 mol) and carbon tetrabromide (73 g, 0.22 mol) were added to a solution of N- (2-cyanoethyl) -N - [(1S) -phenylethyl] -3-amino- 1,2-propanediol (24.8 g, 0.1 mol) in benzene (400 ml) and the mixture was heated to 90 ° C with stirring. The supernatant was taken off, the solvent was evaporated and the residue obtained was chromatographed on silica gel. A 38 g portion (100%) of the title compound was obtained from the eluate (n-hexane: ethyl acetate = 4: 1).
¹ H-NMR _(CDCl3) δ: 1.43 to 1.46 (3 H, m), 2.35 to 2.44 (2 H, m), 2.82 to 2.96 (3 H, m ), 3.14-3.27 (1H, m), 3.67-4.15 (4H, m), 7.27-7.40 (5H, m).

[Reference Example A-3]

1-cyano-3 - [(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane

To a solution of N- (2-cyanoethyl) -N - [(1S) -phenylethyl] -3-amino-1,2-dibromopropane (37.4 g, 0.1 mol) in toluene (700 ml) was added dropwise add a 1M solution of sodium (bistrimethylsilyl) amide in tetrahydrofuran (220 mL, 0.22 mol) while cooling with an ice bath, and stir the mixture at the same temperature for 20 minutes. After completion of the reaction, a saturated aqueous ammonium chloride solution (100 ml) was added dropwise to the reaction solution, which was then allowed to warm to room temperature. The organic layer was taken, washed with a saturated saline solution and then dried over sodium sulfate. The solvent was evaporated and the resulting residue was subjected to chromatography on silica gel. A 7.93 g portion (37%) of the lower polarity title compound (Fr. 1) was obtained from the eluate (n-hexane: ethyl acetate = 9: 1) followed by 7.85 g (36%) of the Title compound with the higher polarity (Fr. 2).

1;
¹ H-NMR _(CDCl3) δ: 1.09 (1 H, dd, J = 4.5, 8.3 Hz), 1.29 (3 H, d, J = 6.4 Hz), 1, 57 (1H, t, J = 4.5 Hz), 1.95-1.99 (1H, m), 2.27 (1H, dd, J = 3.9, 9.8 Hz), 2.61 (1H, d, J = 8.8Hz), 2.68 (1H, d, J = 9.8Hz), 3.33-3.38 (2H, m), 7, 21-7.31 (5H, m).

2;
¹ H-NMR (CDCl ₃ ) δ: 1.09 (1 H, dd, J = 4.9, 8.3 Hz), 1.29 (3 H, d, J = 6.4 Hz), 1, 55-1.58 (1H, m), 2.04-2.09 (1H, m), 2.35 (1H, d, J = 8.8Hz), 2.53 (1H, dd, J = 3.9, 9.3 Hz), 2.86 (1 H, d, J = 9.3 Hz), 3.18 (1 H, d, J = 9.3 Hz), 3, 32-3.37 (1H, m), 7.21-7.32 (5H, m).

[Reference Example A-4]

3 - [(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane-1-carboxylic acid (Ms. 1)

To a solution of 1-cyano-3 - [(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane (m.p. 5.6 g, 26.4 mmol) in methanol (50 ml) was added a 2N aqueous sodium hydroxide solution (50 ml) and heated the mixture is refluxed for 30 hours. The methanol was evaporated and the residue obtained was washed with chloroform (30 ml x 2), placed with concentrated hydrochloric acid the pH to 3 and then extracted with n-butanol (80 ml x 3). The Extract dried over Sodium sulfate and then the solvent was evaporated, yielding 6.11 g (100%) of the crude title compound. This became direct in the subsequent Implementation used.

[Reference Example A-5]

3 - [(1S) -phenyl-ethyl-3-azabicyclo [3.1.0] hexane-1-carboxylic acid (Ms. 2)

Fr. 2 was subjected to the same reaction as in Reference Example A-4.

[Reference Example A-6]

1-tert-butoxycarbonylamino-3 - [(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane (Fr. 1)

Diphenylphosphoryl azidate (9.99 g, 34.3 mmol) and triethylamine (4.23 g, 36.9 mmol) were added to a solution of 3 - [(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane 1-carboxylic acid (Fr.1, 6.11g, 26.4mmol) in t-butanol (200ml) and the mixture was heated at reflux for 4 hours. After cooling, the solvent was evaporated and the resulting residue was mixed with 200 ml of ethyl acetate. The mixture was washed with saturated brine (50 ml x 2) and then dried over sodium sulfate. The solvent was evaporated and the resulting residue was subjected to chromatography on silica gel. A 3.19 g portion (40%) of the title compound was obtained from the eluate (n-hexane: ethyl acetate = 4: 1).
¹ H-NMR _(CDCl3) δ: 0.67 to 0.71 (1 H, m), 1.25-1.31 (4 H, m), 1.45 (9 H, s), 1, 60 (1H, brs), 2.30-2.38 (1H, m), 2.51-2.58 (2H, m), 3.20-3.35 (2H, m), 4.96 (1H, brs), 7.20-7.29 (5H, m).

[Reference Example A-7]

1-tert-butoxycarbonylamino-3 - [(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane (2)

2 was subjected to the same reaction as in Reference Example A-6.
¹ H-NMR _(CDCl3) δ: 0.69 to 0.71 (1 H, m), 1.25 (3 H, d, J = 6.4 Hz), 1.39 (9 H, S) , 1.50-1.72 (2H, m), 2.29 (1H, d, J = 8.3Hz), 2.58-2.82 (2H, m), 3.08- 3.15 (1H, m), 3.30-3.38 (1H, m), 4.82 (1H, brs), 7.19-7.37 (5H, m).

[Reference Example A-8]

1-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (Fr. 1)

To a solution of 1-tert-butoxycarbonylamino-3 - [(1S) -phenylethyl] -3-azabicyclo [3.1.0] hexane (m.p. 3.1 g, 10.26 mmol) in ethanol (50 ml) was added 10% palladium on carbon (3 g) and the mixture was subjected to catalytic hydrogenation at 4 atmospheric pressure for 3 hours while heating the reaction vessel with an infrared radiator. The catalyst was removed by filtration and then the solvent was evaporated to give 2.04 g (100%) of the title compound.
¹ H-NMR _(CDCl3) δ: 0.85 to 1.44 (2 H, m), 1.44 (9 H, s), 1.44 to 1.70 (1 H, m), 2, 95-3.34 (4H, m), 5.08 (1H, brs).

[Example 1]

10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1, 2,3-de] [1,4] benzoxazine-6-carboxylic acid (isomer A)

To a solution of 9,10-difluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid BF ₂ chelate (900 mg, 2.74 mmol) in dimethylsulfoxide (10 ml) was added with 1-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (Fr. 1, 800 mg, 4 mmol) and triethylamine ( 690 mg) and the mixture was stirred at room temperature for 23 hours. After vaporizing triethylamine under reduced pressure, the residue thus obtained was mixed with water (80 ml) and stirred for 30 minutes at room temperature. The crystals thus obtained were washed with water, filtered and dissolved in a mixture of methanol: water = 4: 1 (300 ml), and the resulting solution was mixed with triethylamine (20 ml) and heated at reflux for 3.5 hours. The solvent was evaporated under reduced pressure, and the residue thus obtained was mixed with chloroform (300 ml), washed with 10% citric acid (70 ml × 2), and dried over sodium sulfate, followed by evaporation of the solvent under reduced pressure. The residue thus obtained was mixed with concentrated hydrochloric acid (20 ml) and stirred at room temperature for 5 minutes and made alkaline by adding 20% aqueous sodium hydroxide solution and then adjusted to pH 7.2 with concentrated hydrochloric acid and extracted with chloroform (200 ml x 3). The extract was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give 980 mg of the title compound. Recrystallization from a 28% aqueous ammonia-ethanol solution gave 830 mg (85%) of the title compound.
¹ H-NMR (0.1 N NaOD) δ: 0.71-0.74 (1H, m), 0.79-0.83 (1H, m), 1.37-1.41 (1 H, m), 1.45 (3H, d, J = 6.84 Hz), 3.47-3.50 (2H, m), 3.56-3.67 (2H, m), 4.26 (1 H, d, J = 10.74 Hz), 4.43 (1 H, d, J = 10.74 Hz), 4.50-4.60 (1 H, m), 7, 38 (1 H, d, J = 13.67 Hz), 8.30 (1 H, s).
Melting point: 212-216 ° C (decomposition)
[α] _D = -14.45 ° (c = 0.595, 0.1 N NaOH)
Elemental analysis for C ₁₈ H ₁₈ FN ₃ O ₄ :
Calculated: C, 60.16; H, 5.05; N, 11,69
Found: C, 60.13; H, 5:18; N, 11,45.

[Example 2]

8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H- pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (isomer A)

Anmerkung: die Verbindungen A und B weisen jeweils eine 6-Amino-azabicyclo-[3.1.0]hexan-3-yl-Gruppe in der 10-Position auf und die weiteren Substituenten der Verbindung A, abgesehen von dieser Position, sind die gleichen wie die der Verbindung 1 und solche der Verbindung B sind die gleichen wie die der Verbindung 2.To a solution of 8-amino-9,10-difluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine 1-tert-Butoxycarbonylamino-3-azabicyclo [3.1.0] hexane (m.p. 1, 270 mg, 1.36 mmol) and 1-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane Triethylamine (1ml) and heated the mixture at 100 ° C for 24 hours. After evaporation of the solvent under reduced pressure, the residue thus obtained was mixed with chloroform (50 ml), the resulting solution was washed with 10% citric acid (20 ml × 2) and dried over sodium sulfate, followed by evaporation of the solvent under reduced pressure. The residue thus obtained was mixed with concentrated hydrochloric acid (5 ml) and stirred at room temperature for 5 minutes and the mixture was washed with chloroform (30 ml × 3), made alkaline with 20% aqueous sodium hydroxide solution and then the pH was adjusted to 7, 2 with concentrated hydrochloric acid and extracted with chloroform (50 ml x 3). The extract was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give 201 mg of the crude title compound. Recrystallization from a 28% aqueous ammonia-ethanol solution gave 160 mg (63%) of the title compound.
¹ H NMR (0.1N NaOD) δ: 0.65-0.76 (1H, m), 0.78-0.79 (1H, m), 1.33-1.35 (1H, m), 1.40 (3H, d, J = 6.84 Hz), 3.40-3.52 (3H, m), 3.60-3.65 (1H, m), 3, 96 (1H, d, J = 10.74 Hz), 4.27 (1H, d, J = 10.74 Hz), 4.35-4.39 (1H, m), 8.12 ( 1 H, s).
Melting point:> 224 ° C (decomposition)
Elemental analysis for C ₁₈ H ₁₉ FN ₄ O ₄ .0.25H ₂ O:
Calculated: C, 57.06; H, 5:19; N, 14.79
found: C, 56.92; H, 5:27; N, 14.63. Table 2

Note: Compounds A and B each have a 6-amino-azabicyclo [3.1.0] hexan-3-yl group in the 10-position and the other substituents of Compound A other than this position are the same like those of the compound 1 and those of the compound B are the same as those of the compound 2.

commercial applicability

As described in the foregoing, therefore, the compound of the invention has a ausge has demonstrated antibacterial activity against a wide range of Gram-negative and Gram-positive bacteria and shows strong antibacterial activity especially against Gram-positive bacteria, and more particularly against quinolone-resistant bacteria. In addition, the compound of the present invention has both excellent pharmacokinetics and high safety, so that it is an excellent antibacterial agent. Due to the aforementioned excellent properties, the compound of the present invention is useful as an antibacterial agent for treating infectious diseases and can be used effectively for the preparation of medicines.

Claims (8)

Compounds represented by formula (I):

wherein R ^{1 represents} a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may have a substituent selected from a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms; R ^{2 represents} a hydrogen atom or an amino group, wherein the amino group may have one or two substituents selected from a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 6 carbon atoms; and R ^{3 is} hydrogen, phenyl, acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyl, choline, dimethylaminoethyl, 5-indanyl, phthalidinyl, 5-alkyl-2-oxo-1,3-dioxole-4 ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group consisting of an alkylene group having 1 to 6 carbon atoms and a phenyl group; and salts, hydrates and stereochemically pure forms of these compounds. Compounds according to claim 1, wherein R ² in the formula (I) represents a hydrogen atom or an amino group. 10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1, 2,3-de] benzoxazine-6-carboxylic acid Ester, a salt, a hydrate and / or a pure isomer thereof. 8-amino-10- (1-amino-3-azabicyclo [3.1.0] hexan-3-yl) -9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H- pyrido [1,2,3-de] benzoxazine-6-carboxylic acid Ester, a salt, a hydrate and / or a pure isomer thereof. Pharmaceutical preparation as active ingredient at least one of the compounds according to one of claims 1 to 4 contains. Antibacterial agent acting as an active ingredient at least one compound according to one the claims 1 to 4 contains. Use of at least one compound according to one the claims 1 to 4, for the preparation of a pharmaceutical preparation. Use according to claim 7 for the treatment of infectious diseases.